Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell penetrating peptide based gene carriers are notably known for low level of gene transfer. To remedy this, as laminin receptor (LR) has been previously linked to tumor metastasis, the LR-binding domain (YIGSR) as well as a scrambled sequence (SGIYR) were added to Tat-derived peptide sequence (YIGSR-Tat and SGIYR-Tat respectively). Peptides cellular uptake was assessed with high-LR (HT1080) and low-LR (HT29) cell lines by flow cytometry. Their ability to form complexes with DNA was examined using YOPRO-1 fluorescence assay and their transfection efficiencies evaluated using a luciferase reporter gene assay. DNA complexes were formed at (+/-) charge ratios as low as 2:1. While no conclusion could be drawn on the effect of YIGSR sequence on peptides uptake in both cell lines, a significant improvement in gene transfection in HT1080 cells was achieved using YIGSR-Tat compared to Tat and SGIYR-Tat. Additionally this increased efficiency was inhibited by excess free YIGSR. No significant difference in transfection efficiency was observed between Tat, SGIYR-Tat and YIGSR-Tat based complexes in HT29 cells. These studies demonstrate that attachment of receptor-binding ligand (YIGSR) to Tat-derived peptide can improve the efficiency of gene transfer in LR-positive cells (HT1080).
Biopolymers 2008 Jan
PMID:Enhancement of gene transfer using YIGSR analog of Tat-derived peptide. 1790 73

The extracellular matrix (ECM) represents a major barrier for delivery of therapeutic drugs, and the transport is determined by the ECM composition, structure, and distribution. Because of the high interstitial fluid pressure in tumors, diffusion becomes the main transport mechanism through ECM. The purpose of this work was to study the impact of the structure of the collagen network on diffusion, by studying to what extent the orientation and chemical modification of the collagen network influenced diffusion. Collagen gels with a concentration of 0.2-2.0% that is comparable with the amount of collagen in the tumor ECM were used as a model system for ECM. Collagen gels were aligned in a low-strength magnetic field and geometrical confinement, and chemically modified by adding decorin or hyaluronan. Diffusion of dextran 2-MDa molecules in the collagen gels was measured using fluorescence recovery after photobleaching. Alignment of the collagen fibers in our gels was found to have no impact on the diffusion coefficient. Adding decorin reduced the diameter of the collagen fibers, but no effect on diffusion was observed. Hyaluronan also reduced the fiber diameter, and high concentration of hyaluronan (2.5 mg/ml) increased the diffusion coefficient. The results indicate that the structure of the collagen network is not a major factor in determining the diffusion through the ECM. Rather, increasing the concentration of collagen was found to reduce the diffusion coefficient. Concentration of the collagen network is more important than the structure in determining the diffusion coefficient.
Biopolymers 2008 Feb
PMID:Physical and chemical modifications of collagen gels: impact on diffusion. 1795 15

Raman spectroscopy shows potential in differentiating tumors from normal tissue. We used Raman spectroscopy with near-infrared light excitation to study normal breast tissue and tumors from 11 mice injected with a cancer cell line. Spectra were collected from 17 tumors, 18 samples of adjacent breast tissue and lymph nodes, and 17 tissue samples from the contralateral breast and its adjacent lymph nodes. Discriminant function analysis was used for classification with principal component analysis scores as input data. Tissues were examined by light microscopy following formalin fixation and hematoxylin and eosin staining. Discriminant function analysis and histology agreed on the diagnosis of all contralateral normal, tumor, and mastitis samples, except one tumor which was found to be more similar to normal tissue. Normal tissue adjacent to each tumor was examined as a separate data group called tumor bed. Scattered morphologically suspicious atypical cells not definite for tumor were present in the tumor bed samples. Classification of tumor bed tissue showed that some tumor bed tissues are diagnostically different from normal, tumor, and mastitis tissue. This may reflect malignant molecular alterations prior to morphologic changes, as expected in preneoplastic processes. Raman spectroscopy not only distinguishes tumor from normal breast tissue, but also detects early neoplastic changes prior to definite morphologic alteration.
Biopolymers 2008 Mar
PMID:Raman spectroscopy can differentiate malignant tumors from normal breast tissue and detect early neoplastic changes in a mouse model. 1804 Oct 66

Radiotherapy is the choice of treatment for locally advanced stages of the cervical cancers, one of the leading female cancers. Because of intrinsic factors, tumors of same clinical stage and histological type often exhibit differential radioresponse. Radiotherapy regimen, from first fraction of treatment to clinical evaluation of response, spans more than 4 months. Clinical assessment by degree of tumor shrinkage is the only routinely practiced method to evaluate the tumor response. Hence, a need is created for development new methodologies that can predict the tumor response to radiotherapy at an early stage of the treatment which can lead to tailor-made protocols. To explore the feasibility of prediction of tumor radioresponse, Raman spectra of cervix cancer tissues that were collected before (malignant) and 24 h after patient was treated with 2nd fraction of radiotherapy (RT) were recorded. Data were analyzed by Principal Components Analysis (PCA) and results were correlated with clinical evaluation of radioresponse. Mean Raman spectra of RT tissues corresponding to different levels of tumor response, complete, partial, and no response, showed minute but significant variations. The unsupervised PCA of malignant tissues failed to provide any classification whereas RT spectra gave clear classification between responding (complete and partial response) and nonresponding conditions as well as a tendency of separation among responding conditions. These results were corroborated by supervised classification, by means of discrimination parameters: Mahalanobis distance and spectral residuals. Thus, findings of the study suggest the feasibility of Raman spectroscopic prediction of tumor radioresponse in cervical cancers.
Biopolymers 2008 Jun
PMID:Prediction of radiotherapy response in cervix cancer by Raman spectroscopy: a pilot study. 1818 3

The development of receptor targeting radiolabeled ligands has gained much interest in recent years for diagnostic and therapeutic applications in nuclear medicine. Cholecystokinin (CCK) receptors have been shown to be overexpressed in a subset of neuroendocrine and other tumors. We are evaluating binding and biodistribution properties of a CCK8 peptide derivative labeled with (99m)Tc(I)-tricarbonyl. The CCK8 peptide was modified at its N-terminus by adding to its N-terminus two lysine-histidine modules (KH), where histidine is coupled to the side chain of the lysine ((KH)(2)-CCK8). (99m)Tc(I)-tricarbonyl was generated with the IsoLinktrade mark kit. A431 cells stably transfected with a cDNA encoding for the human CCK2 receptor were utilized to determine binding affinity, internalization, and retention of the labeled peptide, in comparison with wild-type A431 cells. A nude mouse tumor model was obtained by generating A431-CCK2R and A431-control tumors in opposite flanks of the animals. High specific activity labeling with (99m)Tc was achieved. In A431-CCK2R cells, specific saturable binding was observed as well as evident internalization of the radiolabeled peptide after binding. Biodistribution experiments showed rapid, specific localization of (KH)(2)-CCK8 on A431-CCK2R xenografts compared with control tumors, although absolute uptake values were not markedly higher compared with background activity. Clearance of unbound radioactivity was both urinary and hepatobiliary. In imaging experiments, while targeting to CCK2R positive tumors could be appreciated, there was poor contrast between target and nontarget areas. (KH)(2)-CCK8 shows adequate in vitro and in vivo properties for CCK2R targeting although improvement of biodistribution warrant further development.
Biopolymers 2008
PMID:In vivo and in vitro characterization of CCK8 bearing a histidine-based chelator labeled with 99mTc-tricarbonyl. 1861 95

The tumor suppressor protein p53 is a tetrameric phosphoprotein that induces cell cycle, development, and differentiation by regulating the expression of target genes. The tetramerization of p53 is essential for its tumor suppressor functions. It has been known that oxidation of proteins affects their structure and function. A methionine residue (Met340) is located at the hydrophobic core in p53 tetramerization domain. Here, we demonstrated that Met340 residue can be oxidized to methionine sulfoxide under oxidative conditions and investigated effects of the oxidation of p53 tetramerization domain on its stability and oligomerization state by CD measurement and gel filtration. The oxidation of Met340 drastically induced destabilization of the p53 tetramer by 22.8 kJ/mol of DeltaDeltaG(Tm), while retaining the identical conformation as that of the wild-type peptide. Trypsin digestion experiments also showed that oxidation of Met340 allowed the peptide to form locally loose structure and become more sensitive to enzyme degradation. The tetrameric structure may be destabilized because the oxidation of Met340 induces charge repulsion and/or steric hindrance between the sulfoxide groups. These results taken together suggested that oxidation of methionine residues in the p53 protein might be one of the inactivation mechanisms of p53 transcriptional function under conditions of oxidative stress.
Biopolymers 2009 Jan
PMID:Oxidation of methionine residue at hydrophobic core destabilizes p53 tetrameric structure. 1878 28

The conformational properties of the Cys-Arg-Glu-Lys-Ala (CREKA) peptide sequence labeled with fluorescein, a fluorescent dye attached to the Cys through a flexible linker have been examined using molecular dynamics simulations. The CREKA sequence has been identified as a tumor-homing peptide that effectively binds to clotted plasma proteins. Before conformational exploration, the molecular geometry, basicity and spectroscopic properties of this dye, which is essential for the imaging the peptide activity, have been examined using quantum mechanical calculations, with the results also allowing determination of the force-field parameters required for classical simulations. Minimum energy conformations derived from the conformational search have been classified using clustering analyses with criteria based on both the existence of interactions and backbone geometric similarity. The results have been compared with those reported for isolated CREKA (peptide without dye). We found that the fluorescein affects the energy distribution of the minimum energy conformations, with the repulsive steric interactions induced by the dye producing shifting the distribution towards higher energy values. Interestingly, although the structural characteristics of the bioactive conformation identified for CREKA are not perturbed by the dye, it is less stable when the peptide is attached to the dye than in other chemical environments previously studied (isolated peptide, peptide attached to the surface of a protein, and peptide inserted in a phage display protein).
Biopolymers 2009
PMID:Influence of the dye presence on the conformational preferences of CREKA, a tumor homing linear pentapeptide. 1905 12

The human epidermal growth factor receptor HER2 has emerged as an important target for molecular imaging of breast cancer. This article presents the design and synthesis of a HER2-targeting affibody molecule with improved stability and tumor targeting capacity, and with potential use as an imaging agent. The 58 aa three-helix bundle protein was assembled using solid-phase peptide synthesis, and a chemoselective ligation strategy was used to establish an intramolecular thioether bond between the side chain thiol group of a cysteine residue, positioned in the loop between helices I and II, and a chloroacetyl group on the side chain amino group of the C-terminal lysine residue. The tethered protein offered an increased thermal stability, with a melting temperature of 64 degrees C, compared to 54 degrees C for the linear control. The ligation did not have a major influence on the HER2 binding affinity, which was 320 and 380 pM for the crosslinked and linear molecules, respectively. Biodistribution studies were performed both in normal and tumor-bearing mice to evaluate the impact of the crosslinking on the in vivo behavior and on the tumor targeting performance. The distribution pattern was characterized by a low uptake in all organs except kidney, and rapid clearance from blood and normal tissue. Crosslinking of the protein resulted in a significantly increased tumor accumulation, rendering the tethered HER2-binding affibody molecule a valuable lead in the development of superior HER2 imaging agents.
Biopolymers 2009
PMID:Synthesis and chemoselective intramolecular crosslinking of a HER2-binding affibody. 1914 Jan 62

Radiolabeled peptides play an important role in radiopharmacy not only as tumor markers but also as transport vectors. Therefore, cell-penetrating peptides (CPP) may serve as very effective delivery tools, as well. Recently, CPP based on the human hormone calcitonin (hCT) have been developed. Especially, branched hCT-peptide sequences turned out to have highly efficient internalization capacities. Labeling these peptides with radionuclides would generate promising new tools for imaging and therapy applications in radiopharmacy. However, the influence of the metal complexation on the internalization capacity of CPP has not been elucidated yet in detail. In this study we quantified the uptake of Ga-DOTA modified hCT-carrier peptides in HeLa cells by using atomic absorption spectroscopy (AAS) and compared the results to the uptake of fluorescently-labeled peptides. Interestingly, we measured different uptake rates depending on the attached label. Unexpectedly, modification with a Ga-DOTA complex can have tremendous effects on the uptake efficiency. The results of these studies support the need of detailed analysis of each carrier peptide/cargo construct, especially in the field of metal complex modified CPP.
Biopolymers 2009
PMID:Specific labeling with potent radiolabels alters the uptake of cell-penetrating peptides. 1939 52

Cortactin is a ubiquitous actin-binding protein that regulates various aspects of cell dynamics and is implicated in the pathogenesis of human neoplasia. The sequence of cortactin contains a number of signaling motifs and an SH3 domain at the C-terminus, which mediates the interaction of the protein with several partners, including Shank2. A recombinant protein, comprising the murine cortactin SH3 domain fused to GST (GST-SH3(m-cort)), was prepared and used to assess the domain-binding affinity of potential peptide-ligands reproducing the proline-rich regions of human HPK1 and Shank2 proteins. The key residues involved in the SH3(m-cort) domain recognition were identified by three different approaches: non-immobilized ligand interaction assay by circular dichroism, isothermal titration calorimetry, and nuclear magnetic resonance. Our results show that the classical PxxPxK class II binding motif is not sufficient to mediate the interaction with GST-SH3(m-cort), an event that depends on the presence of additional basic residues located at either the N- or the C-terminus of the PxxPxK motif. Especially effective in promoting the peptide binding is a Lys residue at the -5 position, a determinant present in both P2 (HPK1 394-403) and S1 (Shank2 1168-1189) peptides. GST-SH3(m-cort) exhibits the highest affinity toward peptide S1, which contains additional Lys residues at the -3, -5, and -7 positions, indicating that the optimal consensus motif may be KPPxPxKxKxK. These results are supported by the in silico models of SH3(m-cort) complexed with P2 or S1, which highlight the domain residues that interact with the recognition determinants of the peptide-ligand and cooperate in binding stabilization.
Biopolymers 2010
PMID:Recognition of lysine-rich peptide ligands by murine cortactin SH3 domain: CD, ITC, and NMR studies. 1992 43


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